17α‐estradiol: a less‐feminizing estrogen

Abstract

Alzheimer's disease (AD) is a major neurodegenerative disorder in the elderly and is the most common form of dementia. Approved AD drugs like donepezil and memantine provide some cognitive benefits to a subset of patients. However, the cost burden of AD will continue to increase in the absence of more effective drugs that treat its symptoms and ultimately slow its progression or delay or prevent its onset. A substantial number of studies report that 17b-estradiol (E2; estrogen), a potent endogenous feminizing hormone, is neuroprotective. Unfortunately, negative results from the Women's Health Initiative (WHI) and its ancillary Memory Study (WHIMS) have overshadowed the positive data collected over several decades. Importantly, there are a number of reasons why the WHIMS results should not be generalized to less-or nonfeminizing estrogens. For the sake of argument, consider ''non-hormonal'' or non-feminizing estrogens to be worthwhile drug development candidates for AD and other neurodegenerative conditions because they have the potential to retain the positive neuroprotective activities of E2 while reducing the potential complications associated with feminizing hormones. Because the literature comparing estrogenicity of various estrogens is complex and spans multiple decades, we summarize herein the available hormonal comparisons of a common less-feminizing estrogen, 17a-estradiol (17aE2), with E2. 17aE2 is less feminizing than E2 in every published study where reasonable comparisons can be made. One-half of these studies report a difference of two orders of magnitude or greater. In practice, compounds like 17aE2 may prove to be largely nonfeminizing at doses to be explored in human clinical trials. Moreover, other novel E2 analogues have been identified that are essentially devoid of feminizing actions. If the positive effects of feminizing estrogens on neurodegeneration prove useful in treating neurodegenerative diseases, less-feminizing and non-feminizing estrogen analogues may be even more effective, safer, and better tolerated. Drug Dev Res 69 : 177-184, 2008.

Review of the effects of 17α‐estradiol in humans: a less feminizing estrogen with neuroprotective potential

“…Furthermore, it would seem prudent to test 17a-estradiol at doses at which it is not feminizing, so that any positive effects could be separated from the known neuroprotection provided by feminizing estrogens. This admonition is simple in concept, but more difficult in practice because the estrogenicity of 17a-estradiol relative to that of 17b-estradiol varies among studies for reasons that are not always clear [Moos et al, 2008]. In spite of the potential technical challenges of such studies, the cumulative information on safety, efficacy, and PK of 17a-estradiol-especially given the lack of drugs for neuroprotection-make them attractive.…”

“…As summarized above, the less feminizing (see, e.g., Littlefield et al [1990] and Moos et al [2008]) 17a isomer (in its free and sulfate conjugate form) of the potent natural hormonal estrogen 17b-estradiol has had extensive exposure in humans, and the literature records a long history of sometimes contradictory animal and human studies. Nonetheless, 17a-estradiol is an orally available, small-molecule drug, with efficacy in some relevant preclinical models that may be predictive of therapeutic potential in human neurodegenerative diseases.…”

“…The estrogen 17a-estradiol is a less feminizing isomer of the most potent known natural hormonal estrogen, 17b-estradiol [Moos et al, 2008]. Exposure of humans to 17a-estradiol in various forms and mixtures, including the single agent itself as a sodium salt of the 3-sulfate conjugate (also known as MX-4509; , has been extensive, as outlined herein.…”

“…Given that 17a-estadiol is (1) as good as or better than 17b-estradiol in some preclinical studies, (2) more selective in its other physiological effects, (3) apparently less toxic, and (4) less feminizing than the hormonal estrogens that are the focus of many published human studies [Moos et al, 2008], it represents an attractive compound for studying the efficacy and safety of members of this chemical class in humans. At present, however, this possibility has not been adequately tested, and as noted above, the available studies are inconsistent, and some yield no significant evidence of neuroprotection.…”

“…Compared with 17b-estradiol, 17a-estradiol is active at similar concentrations and doses in numerous in vitro and in vivo model systems of neuroprotection [see, e.g., Howell et al, 2005a;Moos et al, 2008]. Given that 17a-estadiol is (1) as good as or better than 17b-estradiol in some preclinical studies, (2) more selective in its other physiological effects, (3) apparently less toxic, and (4) less feminizing than the hormonal estrogens that are the focus of many published human studies [Moos et al, 2008], it represents an attractive compound for studying the efficacy and safety of members of this chemical class in humans.…”